Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
Roche Innovation Center, F. Hoffmann-La Roche AG, Roche Pharma Research and Early Development, Basel, Switzerland.
J Immunother Cancer. 2024 Nov 17;12(11):e009860. doi: 10.1136/jitc-2024-009860.
T cell-based immunotherapies including immune checkpoint blockade and chimeric antigen receptor T cells can induce durable responses in patients with cancer. However, clinical efficacy is limited due to the ability of cancer cells to evade immune surveillance. While T cells have been the primary focus of immunotherapy, recent research has highlighted the importance of natural killer (NK) cells in directly recognizing and eliminating tumor cells and playing a key role in the set-up of an effective adaptive immune response. The remarkable potential of NK cells for cancer immunotherapy is demonstrated by their ability to broadly identify stressed cells, irrespective of the presence of neoantigens, and their ability to fight tumors that have lost their major histocompatibility complex class I (MHC I) expression due to acquired resistance mechanisms.However, like T cells, NK cells can become dysfunctional within the tumor microenvironment. Strategies to enhance and reinvigorate NK cell activity hold potential for bolstering cancer immunotherapy.
In this study, we conducted a high-throughput screen to identify molecules that could enhance primary human NK cell function. After compound validation, we investigated the effect of the top performing compounds on dysfunctional NK cells that were generated by a newly developed in vitro platform. Functional activity of NK cells was investigated using compounds alone and in combination with checkpoint inhibitor blockade. The findings were validated on patient-derived intratumoral dysfunctional NK cells from different cancer types.
The screening approach led to the identification of a Casitas B-lineage lymphoma (Cbl-b) inhibitor enhancing the activity of primary human NK cells. Furthermore, the Cbl-b inhibitor was able to reinvigorate the activity of in vitro generated and patient-derived dysfunctional NK cells. Finally, Cbl-b inhibition combined with T-cell immunoreceptor with Ig and ITIM domains (TIGIT) blockade further increased the cytotoxic potential and reinvigoration of both in vitro generated and patient-derived intratumoral dysfunctional NK cells.
These findings underscore the relevance of Cbl-b inhibition in overcoming NK cell dysfunctionality with the potential to complement existing immunotherapies and improve outcomes for patients with cancer.
基于 T 细胞的免疫疗法，包括免疫检查点阻断和嵌合抗原受体 T 细胞，可在癌症患者中诱导持久的反应。然而，由于癌细胞逃避免疫监视的能力，临床疗效有限。虽然 T 细胞一直是免疫疗法的主要焦点，但最近的研究强调了自然杀伤 (NK) 细胞在直接识别和消除肿瘤细胞以及在建立有效的适应性免疫反应中发挥关键作用的重要性。NK 细胞在癌症免疫治疗中的巨大潜力体现在其能够广泛识别应激细胞，而不论是否存在新抗原，以及其能够对抗因获得性耐药机制而丧失主要组织相容性复合体 I 类 (MHC I) 表达的肿瘤。然而，与 T 细胞一样，NK 细胞在肿瘤微环境中可能会功能失调。增强和重振 NK 细胞活性的策略有可能增强癌症免疫疗法。
在这项研究中，我们进行了高通量筛选，以确定能够增强原代人 NK 细胞功能的分子。在化合物验证后，我们研究了在新开发的体外平台上产生的功能失调的 NK 细胞中，顶级表现化合物的作用。单独使用化合物以及与检查点抑制剂阻断联合使用来研究 NK 细胞的功能活性。在来自不同癌症类型的患者来源的肿瘤内功能失调的 NK 细胞上验证了这些发现。
筛选方法导致鉴定出一种 Casitas B 细胞淋巴瘤 (Cbl-b) 抑制剂，可增强原代人 NK 细胞的活性。此外，Cbl-b 抑制剂能够重振体外生成和患者来源的功能失调的 NK 细胞的活性。最后，Cbl-b 抑制与 T 细胞免疫受体与 Ig 和 ITIM 结构域 (TIGIT) 阻断联合使用进一步增加了体外生成和患者来源的肿瘤内功能失调的 NK 细胞的细胞毒性潜力和重振作用。
这些发现强调了 Cbl-b 抑制在克服 NK 细胞功能失调方面的相关性，具有补充现有免疫疗法和改善癌症患者结局的潜力。
